Computational insights into the structure and dynamics of the human serotonin transporter N-terminus by microsecond molecular dynamics

Background: The human serotonin transporter is an important drug target for the treatment of various medical conditions of which depression is the most important, but also include attention deficit hyperactivity disorder, schizophrenia, social anxiety disorder and irritable bowel syndrome, among others. The transmembrane portion of the human transporter has been studied extensively and first crystalized in 2016. However, the dynamical nature of the N-terminal segment of pro-tein and its post-translational modifications remain insufficiently explored. Objective: The present study aims to evaluate the structure and dynamics of the N-terminal segment of the human serotonin transporter and the presence and stability of possible secondary structure elements along with its post-translational modifica-tions and disorder propensity. Methods: The segment was investigated using a combination of bioinformatics tools for physico-chemical characterization, secondary structure prediction, post-translational modifications and disorder prediction, followed by ab initio modeling and microsecond long explicit solvent molecular dynamics. Results: Our study reveals the presence of metastable secondary structure elements, namely two alpha helices and a beta-sheet, throughout the molecular dynamics run and identifies numerous sites with high probability for post-translational mod-ifications. Conclusion: Our results show that, despite the intrinsically unstructured nature, the N-terminus adopts a stable confor-mation with stable secondary structure elements, that could indicate an important functional role for the segment. Also, there is a high probability that the segment undergoes multiple post-translational modifications.